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Regular Article |
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From the Departments of Internal Medicine,*
Pathology,
and Human Genetics,||
and the Cancer Center,
University of Michigan,
Ann Arbor, Michigan; the Biology Division,
National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; and
the Department of Adult Oncology, Dana-Farber Cancer Institute,
and the Department of Pathology,¶ Brigham &
Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Like other common cancers, colorectal carcinomas are thought to arise
through a multistep process in which repeated cycles of somatic
mutation of cellular genes and clonal selection of variant progeny with
increasingly aggressive growth properties play a prominent
role.6-8
Several of the genetic alterations that
contribute to initiation and progression of colorectal tumors have been
identified, and they include mutation of specific oncogenes such as
K-ras, and tumor suppressor genes, such as p53
and APC.6-8
Loss of heterozygosity (LOH) at
loci on chromosomes 5q, 17p, and/or 18q is frequent in colorectal
carcinomas. In the case of chromosomes 5q and 17p, LOH is presumed to
inactivate the APC and p53 genes, respectively,
whereas the gene(s) targeted for inactivation by 18q LOH remain poorly
understood.7,8
A minority of colorectal carcinomas harbor
DNA mismatch repair defects and manifest a phenotype in which there is
a high frequency of instability at microsatellite sequence tracts.
Microsatellite instability (MSI) is observed in essentially all
colorectal cancers arising in patients with hereditary nonpolyposis
colorectal cancer and in 
10 to 15% of apparently sporadic
colorectal cancers 7-9
. Defects in mismatch repair
function are thought to increase the rate at which cells acquire the
mutations critical in malignant transformation.7-9
For the most part, previous studies of colorectal carcinoma have not sought to directly address the relationship between specific histopathological features and molecular changes. Nevertheless, there is strong evidence that sporadic colorectal carcinomas with MSI are frequently poorly differentiated, right-sided, and associated with a prominent inflammatory infiltrate.2,10-16 In one study, MSI was correlated with carcinomas of the medullary subtype.2
Several studies have implicated alterations in CDX2, a caudal-related homeobox gene encoding a transcription factor, in colorectal tumor development. Mice heterozygous for a germline, inactivating mutation of the Cdx2 gene develop multiple polyps in the small intestine and colon, with most prominent involvement of the proximal colon.17-19 The morphological features of the polyps in Cdx2+/- mice seem complex, but the lesions have recently been hypothesized to result from a complete loss of Cdx2 expression and function, with consequent reprogramming of intestinal differentiation and regeneration of epithelial cell types normally found in proximal regions of the gastrointestinal tract (eg, stomach and esophagus).19 Inactivating mutations in the CDX2 gene seem to be very rare in human colorectal cancers, although a reduction of CDX2 transcripts has been seen in some human colorectal cancer cell lines and high-grade colonic dysplasias and invasive carcinomas.20-23
In preliminary immunohistochemical studies, we noted loss of CDX2 expression more frequently in poorly DACs than in more well differentiated tumors (ER Fearon, E Macri, and M Loda, unpublished data). We sought to further address the potential contribution of CDX2 alterations in colorectal carcinomas and chose to characterize CDX2 expression in a subset of poorly differentiated colonic carcinomas that we term "large cell minimally differentiated carcinomas" (LCMDCs). These tumors likely include lesions of the type previously described as medullary adenocarcinomas. To address the relationship of LCMDCs to more typical adenocarcinomas, we compared the frequency of several molecular alterations in LCMDCs to those present in DACs. In addition to studying CDX2 expression, tumors were evaluated for K-ras mutations; the MSI phenotype; LOH on chromosomes 5q, 17p, and 18q; and altered expression of the ß-catenin and p53 proteins.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study was conducted with approval from the University of Michigan’s Institutional Review Board. Fifteen LCMDCs and 25 typical DACs accessioned at the University of Michigan between 1988 and 1995 were obtained from the Surgical Pathology archives. The histopathology of each tumor was reviewed by two surgical pathologists (HDA and PCL). All LCMDCs were interpreted as primary colorectal carcinomas based on an in situ component and/or the presence of recognizable, albeit minimal, glandular differentiation in at least a portion of the tumor specimen. In addition, the available clinical record did not indicate the diagnosis of another primary cancer in any of the patients. Five consecutive 5-µm formalin-fixed tissue sections were cut from each paraffin block, mounted on glass slides, then weakly stained with hematoxylin. Specific regions (neoplastic versus non-neoplastic tissue) were carefully microdissected with 22-gauge needles under a light microscope, using adjacent Hematoxylin and eosin-stained sections as dissection guides. Genomic DNA was extracted from microdissected neoplastic tissue and matched non-neoplastic tissue using standard methods.24
CDX2 Antibody
A polyclonal antiserum against the human CDX2 protein was generated by immunizing a rabbit with a purified recombinant fusion protein in which CDX2 amino acids 2 to 194 were fused to glutathione-S-transferase sequences. This region of CDX2 lacks the sequence-specific DNA-binding homeobox domain and shares only limited similarity with other mammalian caudal-related proteins (eg, CDX1). After five booster immunizations, each separated by 3 weeks, CDX2-specific IgG fractions were immunoaffinity purified by incubation with an independent, albeit related, recombinant CDX2 protein immobilized to 4% cross-linked beaded agarose support (AminoLink Plus Immobilization Kit; Pierce, Rockford, IL). This latter recombinant CDX2 fusion protein contained human CDX2 amino acids 2 to 164 fused to a hexahistidine (His6) peptide. The specificity of the affinity-purified anti-CDX2 antibody was tested by Western blot, immunofluorescent, and immunohistochemical studies of human kidney 293 cells engineered to overexpress CDX2 and human colon cancer cell lines known to express variable levels of endogenous CDX2 transcripts. Specificity of the antibody was also assessed by immunohistochemical staining of normal adult colonic mucosa.
Immunohistochemical Staining
Formalin-fixed, paraffin-embedded tissues were sectioned at 5 µm and deparaffinized in two changes of xylene for 10 minutes each. Sections were hydrated into distilled water through a series of graded alcohols. Antigen enhancement was performed by boiling slides in a microwave oven for 10 minutes in citrate buffer diluted to 1x from 10x Antigen Retrieval Citra Solution (Biogenex, San Ramon, CA). Endogenous peroxidase activity was blocked by incubation with 6% hydrogen peroxide in methanol. Slides were washed three times in phosphate-buffered saline (PBS) and then incubated with blocking serum for 10 minutes in a humidified chamber. After additional PBS washes, slides were incubated overnight at 4°C with primary antibody. Affinity-purified, polyclonal rabbit antibody to CDX2 was used at 100-fold dilution; the DO-7 mouse monoclonal antibody against p53 (Novocastra Laboratories Ltd./Vector Laboratories, Inc., Burlingame, CA), was used at 25-fold dilution; and the C19220 mouse monoclonal antibody against ß-catenin (Transduction Laboratories, Lexington, KY) was used at a dilution of 1:500. After washing in PBS, slides were incubated with biotinylated goat anti-rabbit or biotinylated goat anti-mouse secondary antibodies for 30 minutes at room temperature. Antigen-antibody complexes were detected with the avidin-biotin-peroxidase method using diaminobenzidine as a chromogenic substrate (Vectastain ABC-Immunostaining Kit; Vector Laboratories, Inc.), as recommended by the manufacturer. Sections were lightly counterstained with hematoxylin, then evaluated by light microscopy. Each tumor section contained normal colonic mucosa as an internal control. A negative control in which primary antibody was omitted was performed with each staining.
K-ras Mutation Analysis
A 162-bp segment of the K-ras gene encompassing codons 1 to 36 was amplified using primers K1a (5'-GGCCTGCTGAAAATGACTGA) and K1b (5'-GTCCTGCACCAGTAATATGC).25 Genomic DNA templates were suspended in a total volume of 50 µl of reaction buffer containing 20 mmol/L Tris-HCl (pH 8.4), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 200 mmol/L of each primer, 200 µmol/L of each deoxynucleotide triphosphate, and 2.5 U of Taq DNA polymerase (Life Technologies, Gaithersburg, MD). Polymerase chain reaction (PCR) conditions were as follows: 60 seconds at 94°C, 60 seconds at 55°C, and 90 seconds at 72°C for 35 cycles, followed by 10 minutes at 72°C. PCR products were electrophoretically separated on 2% agarose gels, purified with QIAquick Gel Extraction kits (Qiagen, Valencia, CA), and directly sequenced by ThermoSequenase-radiolabeled terminator cycle-sequencing (Amersham Pharmacia Biotech, Piscataway, NJ) according to the manufacturer’s instructions. Each result was confirmed by independent PCR and direct sequencing.
MSI Analysis
We used the MSI criteria and primers defined at "The
International Workshop on Microsatellite Instability and RER Phenotypes
in Cancer Detection and Familial Predisposition."26
The
initial panel of microsatellite loci studied included two
mononucleotide repeats (BAT25 and BAT26)
and three dinucleotide repeats (D2S123,
D5S346, and D17S250). In a subset of the
specimens, analysis was performed with additional markers
(BAT40 and D18S55). PCR was performed in 20-µl
reaction mixtures containing 20 mmol/L Tris-HCl (pH 8.4), 50 mmol/L
KCl, 1.5 mmol/L MgCl2, 200 nmol/L of each primer,
200 µmol/L of each deoxynucleotide triphosphate, 1.5 µCi
of[
-32P]dCTP (Amersham Pharmacia Biotech),
and 0.25 U of Taq DNA polymerase. DNA fragments for each
microsatellite locus were amplified for 35 cycles of 94°C for 60
seconds, 55°C for 60 seconds, and 72°C for 90 seconds followed by a
final extension for 10 minutes at 72°C. PCR products were diluted
10-fold in denaturing buffer containing 95% formamide and 10 mmol/L
ethylenediaminetetraacetic acid and then denatured at 90°C for 3
minutes. Two µl of denatured sample was electrophoresed on 5%
polyacrylamide/6 mol/L urea gels, and visualized by autoradiography.
Tumors were classified as follows: high-frequency MSI (MSI-H), when
more than one third of the evaluable markers showed instability; MSI-L,
when less than one third of evaluable markers showed instability; or
microsatellite stable (MSS), when none of the markers showed
instability.
LOH Analysis
DNA samples from tumor tissues were analyzed for LOH at specific
loci by comparison with DNA from matched normal tissues. The genotype
at polymorphic microsatellite sequences was assessed by PCR
amplification using the following primer sets: D5S592
(5q22.1), D5S1384 (5q22.2-22.3), TP53 (17p13.1),
D17S1303 (17p13.1-13.3), D18S499
(18q21.32-21.33), and D18S814 (18q21.32-21.33). Detailed
information on the markers can be obtained from the Genome Data Base
(http://gdbwww.gdb.org/). Genomic DNA templates were
suspended in a total volume of 20 µl of PCR buffer containing 67
mmol/L Tris-HCl (pH 8.8), 16 mmol/L
(NH4)2SO4,
0.01% Tween-20, 1.5 or 3.0 mmol/L MgCl2, 200
µmol/L of each deoxynucleotide triphosphate, 1.5 µCi of
[-32P]dCTP, and 0.25 U of Taq DNA
polymerase. Target DNA sequences were amplified using an initial
denaturation step at 95°C for 2 minutes followed by 30 cycles of
94°C for 45 seconds, 55 or 57°C for 45 seconds, and 72°C for 1
minute, with a final extension step at 72°C for 7 minutes. PCR
products were resolved by electrophoresis on 5% denaturing
polyacrylamide-sequencing gels. LOH was scored when there was a
relative decrease (>50%) in the intensity of the signal of one allele
in the tumor compared with the allele signal in matched normal DNA.
Tumors were scored as uninformative when only one allele was present in
DNA from matched normal tissue.
Statistical Analysis
The relationship between molecular features and histological type of carcinoma was tested by Fisher’s exact test. The relationship between survival time and cohort characteristics were estimated by the Kaplan-Meier method, and the resulting curves were compared using the log-rank test. A 5% significance level was used for all tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The 15 patients with LCMDCs ranged in age from 30 to 83 years
(mean, 64.3 years) (Table 1)
. The
30-year-old patient had a long-standing history of Crohn’s disease.
Nine patients were female and six were male. The LCMDCs were
predominantly right-sided, with 13 of the 15 arising in the cecum or
ascending colon. Histologically, the neoplastic cells in LCMDCs were
large, polygonal, and characterized by central chromatin clearing and
prominent nucleoli. The cells were arranged in solid sheets, nests, or
trabeculae with only rare foci of tubular differentiation (Figure 1A)
. A prominent intratumoral and/or
peritumoral lymphocytic infiltrate was often, but not always, present.
In contrast, typical DACs showed overt glandular differentiation
throughout the tumor, with tubules of varying shapes and sizes
lined by tall columnar epithelial cells with variable mucin content
(Figure 1B)
.
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Nine of the 15 (60.0%) LCMDCs had instability at more than two
loci and were classified as MSI-H (Tables 1 and 2)
. The remaining six cases showed no
instability at any of the loci examined (MSS). To investigate the basis
for the MSI-H phenotype, we performed immunohistochemical studies of
the expression of two mismatch repair proteins previously found to be
altered in MSI-H cases, namely MLH1 and MSH2.27-29
Although all six LDMDCs that showed no instability had strong nuclear
staining for MLH1 (example in Figure 2C
),
loss of MLH1 expression was seen in all nine LCMDCs with the MSI-H
phenotype (example in Figure 2D
). All 15 LCMDCs showed strong nuclear
staining for MSH2 (example in Figure 2G
). Mutations at K-ras
codons 12 and 13 were assessed by sequence analysis and were identified
in 2 of 15 tumors (13.3%) (Table 1)
. Both tumors had the same mutation
at K-ras codon 13 [GGT (Gly) 
GAC (Asp)]. LOH on
chromosomes 5q, 17p, and 18q was determined, because LOH of these
chromosomes has been frequently seen in primary colorectal carcinomas.
LOH on chromosomes 5q, 17p, and 18q was identified in 3 of 11 (27.3%),
2 of 10 (20.0%), and 5 of 11 (45.5%) informative tumors, respectively
(Tables 1 and 3)
.
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All 15 LCMDCs were evaluated for CDX2 expression by
immunohistochemistry. Consistent with previous findings,20
we found CDX2 was chiefly localized to the nuclei of normal intestinal
epithelial cells. In each tumor section, normal colonic mucosa was
present and displayed intense immunoreactivity in epithelial nuclei
(score of +3), serving as a useful internal positive control for each
specimen. Compared to adjacent normal mucosa, all 15 LCMDCs showed
reduced expression of CDX2 (Table 4)
.
Eleven tumors (73.3%) lacked any detectable CDX2
reactivity in the nuclei of neoplastic cells (score of 0, Figure 1C
).
Two tumors showed weak CDX2 immunoreactivity in nuclei of neoplastic
cells (score of 1+) and two showed moderate reactivity (score of 2+,
Figure 1D
). We also evaluated p53 expression in LCMDCs by
immunohistochemistry. Five of 15 LCMDCs (33.3%) revealed intense
nuclear staining (score of 3+) for p53 (Figure 1E)
, consistent with the
presence of a mutant p53 protein with prolonged half-life (Table 4)
.
Eight cases showed no detectable p53 reactivity (score of 0, Figure 1F
), and one case each showed weak (score of 1+) or moderate (score of
2+) staining. In contrast to the membrane pattern of ß-catenin
reactivity seen in normal colonic mucosa, all 15 LCMDCs showed markedly
increased levels of ß-catenin in the cytosol and/or nucleus (Figure 2A)
, consistent with the known consequences of inactivating mutations
in the APC or axin genes or activating mutations in ß-catenin in
colon cancers.30-34
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Studies analogous to those described above were performed on 25
DACs (Table 4)
. Although nuclear CDX2 expression was markedly reduced
or absent (score of 0 or 1+) in 13 of 15 (87%) LCMDCs, reduced CDX2
expression was seen in only 1 of the 25 (4%) DACs. This difference was
statistically significant (P < 0.001).
Representative DACs showing retention and loss of CDX2 expression are
shown in Figure 1, G and H
, respectively. Strong reactivity for p53
(score of 3+) was observed in 11 of 25 (44%) DACs (example in Figure 1I
), whereas 14 of the 25 (56%) showed no p53 immunoreactivity (Figure 1J)
. The data on p53 immunoreactivity revealed no significant
difference between LCMDCs and DACs (P = 0.74).
Similarly, as was seen in all 15 LCMDCs, all 25 DACs showed markedly
increased cytoplasmic and/or nuclear staining for ß-catenin (example
in Figure 2B
), indicating that defects in the Wnt/APC/ß-catenin
pathway are common to both LCMDCs and DACs. Consistent with data in the
literature, 2 (8%) and 11 (44%) DACs had the MSI-H phenotype and
K-ras mutations, respectively.35
Although all
DACs showed strong nuclear expression of MSH2 (example in Figure 2H
),
one of the two DACs with the MSI-H phenotype had lost MLH1 expression
(Figure 2F)
and the remaining 23 DACs of MSS/MSI-L phenotype all showed
strong nuclear expression of MLH1 (Figure 2E)
. The decreased frequency
of K-ras mutations in LCMDCs compared to DACs was not statistically
significant (P = 0.08; Table 4
). However,
compared to DACs, LCMDCs were far more frequently characterized by the
MSI-H phenotype and loss of MLH1 expression (P =
0.002).
Survival data were available for 24 of the 25 patients with DACs and 14
of the 15 patients with LCMDCs. The average follow-up interval for the
surviving patients was 5.4 years (range, 1.5 to 10.1 years). For the
deceased patients, the average follow-up was 2.2 years (range, 0.1 to
9.2 years). Of the 14 patients with LCMDCs for whom follow-up
information was available, 8 had died at the time of follow-up (seven
with disease, one without disease). Of the 24 patients with DACs for
whom survival data were available, 14 had died at the time of follow-up
(nine with disease, five without disease). Kaplan-Meier survival
estimates showed the difference between the survival of patients with
LCMDCs and DACs was not statistically significant
(P = 0.345, log-rank test). Kaplan-Meier
survival estimates also indicated that there were no
statistically significant relationships observed
between survival and CDX2 expression, p53 expression, K-ras
mutation, or MSI (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the studies presented here, we chose to analyze the molecular features of a group of poorly differentiated colorectal cancers with a distinct histopathological appearance that we term LCMDCs. Nearly all LCMDCs showed loss of CDX2 protein. In addition, when compared to typical DACs, LCMDCs far more frequently manifested the MSI-H phenotype. The frequent loss of CDX2 protein in LCMDCs does not seem to be simply a reflection of poor differentiation, because substantial levels of CDX2 expression were observed in two LCMDCs and CDX2 expression was often observed in other types of poorly differentiated colorectal carcinomas, such as small-cell undifferentiated carcinomas and poorly differentiated carcinomas with sarcomatoid or squamoid features (Fearon laboratory, unpublished observations).
Whether the lesions that we term LCMDCs are analogous to the colorectal cancers that have been termed by others as "medullary adenocarcinomas" is unclear at this point. To date, only a total of 24 colorectal medullary adenocarcinomas appear to have been described in the literature in any detail. Jessurun and colleagues1,39 were the first to report on this entity. They describe medullary adenocarcinomas as comprised of small intermediate-sized, round to polygonal uniform cells with scant eosinophilic or amphophilic cytoplasm, rounded nuclei, chromatin clearing, and small central nucleoli. Most, but not all of the tumors characterized by Jessurun and colleagues1,39 were accompanied by a prominent intratumoral and peritumoral inflammatory response. Tumors were recognized as medullary if at least 80% of the neoplastic cells exhibited a solid, nested, organoid, or trabecular growth pattern. Jessurun and colleagues1,39 also noted a striking predominance of the neoplasm in women (11 of 11), location in the cecum or ascending colon, and relatively favorable prognosis. Rüschoff and co-workers2 have reported 13 additional medullary adenocarcinomas. They compared poorly differentiated adenocarcinomas of the medullary type (with uniform cells) to another group of poorly differentiated colorectal cancers, albeit tumors that had a high degree of cellular pleomorphism. Although the medullary adenocarcinomas in the Rüschoff series also showed a predilection for involvement of the cecum or ascending colon, this was not uniform, as one lesion arose in the transverse colon, and another in the rectum. Moreover, 6 of the 13 lesions arose in men. All 13 lesions lacked strong p53 immunoreactivity (presumably indicating wild-type p53 protein) and the tumors uniformly exhibited MSI. Comparison of the Rushoff and colleagues2 findings on medullary adenocarcinomas to the LCMDCs in our study indicates both similarities and differences. Similar to the Rüschoff and colleagues2 findings on medullary adenocarcinomas, the clinicopathological features of our LCMDCs were not entirely homogeneous, although we observed that LCMDCs were usually right-sided and more often affected women. Molecular features of LCMDCs were overlapping with but distinct from those seen in the medullary adenocarcinomas of Rüschoff and colleagues.2 Specifically, we found LCMDCs commonly but not invariably had the MSI phenotype, and stabilization of p53 protein was observed in a third of our cases.
In our study, the survival of patients with LCMDCs was not significantly different from that of patients with DACs, perhaps reflecting the relatively small number of patients of each type studied. However, because patients with medullary adenocarcinomas have been suggested to have a more favorable prognosis than patients with other poorly differentiated colorectal adenocarcinomas,2,4 it is possible that LCMDCs may constitute a somewhat more clinically and biologically heterogeneous group than medullary adenocarcinomas. Consistent with this proposal, as noted above, MSI was seen in 60% of our LCMDCs, whereas Rüschoff and colleagues2 report MSI to be a uniform feature of their medullary adenocarcinomas. Nevertheless, the observation that CDX2 expression was lost in nearly all LCMDCs implies that certain molecular changes may be characteristic of the pathogenesis of this subgroup. Evaluation of CDX2 expression in the tumors previously described as medullary adenocarcinomas might shed additional light on the relationship between medullary adenocarcinomas and LCMDCs. Moreover, clarification of the mechanisms underlying loss of CDX2 expression should improve understanding of the pathogenesis of colorectal tumors, especially LCMDCs.
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Footnotes |
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Supported by National Institutes of Health (grant RO1CA82223) and in part by the Naito Foundation (Japan) (to T. H.).
T. H. and M. T. contributed equally to this study.
Accepted for publication September 18, 2001.
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